Oily cold water fish, such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids. Omega-3 fatty acids have previously been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been shown to improve in overweight hypertensive subjects through treatment with omega-3 fatty acids. Omega-3 fatty acids (EPA/DHA) have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as dietary supplements part of therapy used to treat dyslipidemia, and anti-inflammatory properties. A higher intake of omega-3 fatty acids lower levels of circulating TNF-α and IL-6, two of the cytokines that are markedly increased during inflammation processes (Chapkin et al, Prostaglandins, Leukot Essent Fatty Acids 2009, 81, p. 187-191; Duda et al, Cardiovasc Res 2009, 84, p. 33-41). In addition, a higher intake of omega-3 fatty acids has been shown to increase levels of the well-characterized anti-inflammatory cytokine IL-10 (Bradley et al, Obesity (Silver Spring) 2008, 16, p. 938-944). A recent study (Wang et al, Molecular Pharmaceutics 2010, 7, p. 2185-2193) has demonstrated that DHA could also induce the Nrf2 and the Nrf2-target gene Heme-oxygenase 1 (HO-1) and this pathway could play a significant role in suppressing LPS-mediated inflammation.
Both DHA and EPA are characterized as long chain fatty acids (aliphatic portion between 12-22 carbons). Medium chain fatty acids are characterized as those having the aliphatic portion between 6-12 carbons. Lipoic acid is a medium chain fatty acid found naturally in the body. It plays many important roles such as free radical scavenger, chelator to heavy metals and signal transduction mediator in various inflammatory and metabolic pathways, including the NF-κB pathway (Shay, K. P. et al. Biochim. Biophys. Acta 2009, 1790, 1149-1160). Lipoic acid has been found to be useful in the treatment of a number of chronic diseases that are associated with oxidative stress (for a review see Smith, A. R. et al Curr. Med. Chem. 2004, 11, p. 1135-46). Lipoic acid has now been evaluated in the clinic for the treatment of diabetes (Morcos, M. et al Diabetes Res. Clin. Pract. 2001, 52, p. 175-183) and diabetic neuropathy (Mijnhout, G. S. et al Neth. J. Med. 2010, 110, p. 158-162). Lipoic acid has also been found to be potentially useful in treating cardiovascular diseases (Ghibu, S. et al, J. Cardiovasc. Pharmacol. 2009, 54, p. 391-8), Alzheimer's disease (Maczurek, A. et al, Adv. Drug Deliv. Rev. 2008, 60, p. 1463-70) and multiple sclerosis (Yadav, V. Multiple Sclerosis 2005, 11, p. 159-65; Salinthone, S. et al, Endocr. Metab. Immune Disord. Drug Targets 2008, 8, p. 132-42).
Fumaric acid and its ester derivatives, either the mono alkyl hydrogen fumarates or dialkyl fumarates, have been used as therapeutic agents for the treatment of psoriasis, an autoimmune and Th1-mediated skin disease (Altmeyer et al, J. of the American Academy of Dermatology 1994, 30, p. 977-981). In clinical studies with psoriasis patients that have been administered with fumarates, a reduction of peripheral CD4+ and CD8+-T lymphocytes has been observed. These agents have been reported to inhibit LPS-induced NF-κB activation in dendritic cells and endothelial cells in vitro (Loewe et al., J. Immunol. 2004, 168, 4781-4787; Litjens et al., Eur. J. Immunol. 2004, 34, 565-575). Dialkyl and monoalkyl fumarates have also demonstrated oral efficacy in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model for multiple sclerosis (MS). In this particular model, C57BL/6 mice were challenged with the immunopeptide MOG 35-55 in order to induce disabilities that were equivalent to those exhibited by MS patients. Oral treatment with either dialkyl or monoalkyl fumarate resulted in a significant improvement in the disability score. The anti-inflammatory cytokine IL-10 was particularly elevated in the blood among the animals treated with either dialkyl or monoalkyl fumarate. Furthermore, histological analysis of the spinal cord of animals treated with either dialkyl or monoalkyl fumarate showed a strongly reduced macrophage inflammation (Schilling et al., Clinical and Experimental Immunology 2006, 145, 101-107). Dialkyl and monoalkyl fumarate esters have also been used in a number of reported studies with patients exhibiting the relapsing-remitting form of multiple sclerosis. Patients treated with 720 mg of fumarate esters daily for 70 weeks exhibited a significant reduction in inflammatory brain lesions, as noted by the reduction of new gadolinium-enhancing (Gd+) lesions in various MRI taken during the course of the treatment (Schimrigk et al., Eur. J. Neurology 2006, 13, 604-610). More recently, fumarates have been shown to activate Nrf2, a transcription factor that is responsible for the induction of a number of important antioxidants and detoxification enzymes that protect mammalian cells against reactive oxygen/nitrogen species and electrophiles (Lukashev, M. E. “Nrf2 screening assays and related methods and compositions” WO 08097596 A2; Wilms et al, Journal of Neuroinflammation 2010, 7:30).
Chronic oxidative stress and inflammation have now been linked to the development and progression of a number of debilitating diseases beyond multiple sclerosis. Some of these diseases include renal failure, heart failure, atherosclerosis, osteoporosis, cancer, chronic obstructive pulmonary disease (COPD), Parkinson's disease and Alzheimer's disease. Activation of the Nrf2 pathway in order to resolve this chronic oxidative stress and inflammation appears to be a particularly promising new therapeutic approach (For a review see Gozzelino, R. et al Annu. Rev. Pharmacol. Toxicol. 2010, 50, p. 323-54). For instance, small molecule activators of Nrf2 have now been shown to be effective in the cisplatin-induced nephrotoxicity mouse model (Aleksunes et al, J. Pharmacology & Experimental Therapeutics 2010, 335, p. 2-12), the transgenic Tg19959 mouse model of Alzheimer's disease (Dumont et al, J. Neurochem. 2009, 109, p. 502-12), the mouse model for COPD (Sussan, T. E. et al Proc. Natl. Acad. Sci. USA 2009, 106, p. 250-5), and the murine 4T1 breast tumor model (Ling, X. et al Cancer Res. 2007, 67, p. 4210-8).
The ability to provide the effects of fatty acids and fumarates in a synergistic way would provide benefits in treating a variety of cancer, metabolic, autoimmune and neurodegenerative diseases.